CN102985926B - Sterility treatment is assessed the system of multiple birth risk - Google Patents

Sterility treatment is assessed the system of multiple birth risk Download PDF

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CN102985926B
CN102985926B CN201180033899.1A CN201180033899A CN102985926B CN 102985926 B CN102985926 B CN 102985926B CN 201180033899 A CN201180033899 A CN 201180033899A CN 102985926 B CN102985926 B CN 102985926B
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CN102985926A (en
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梅林·姚
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UNIVFY Inc
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B17/42—Gynaecological or obstetrical instruments or methods
    • A61B17/425—Gynaecological or obstetrical instruments or methods for reproduction or fertilisation
    • A61B17/435—Gynaecological or obstetrical instruments or methods for reproduction or fertilisation for embryo or ova transplantation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
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Abstract

The invention provides a kind of multiple birth prognostic tool, described instrument accepts the multiple birth event of the female patient of sterility treatment for analytical data with prediction.Described MBP prognostic tool can also be used for improving the diagnosis being predicted embryo survival ability or the accuracy of prognostic assay.The MBP prognostic tool of the present invention can be special clinic, or it also can be modified for multiple multi-clinic approach.

Description

Sterility treatment is assessed the system of multiple birth risk
The cross reference of related application
The present invention advocates the rights and interests of the 61/363rd, No. 650 U.S. Provisional Patent Application case submitted on July 13rd, 2010, and described application case is incorporated herein by reference in full.
Technical field
The present invention relates generally to sterility treatment.The method that more precisely, the invention relate to the multiple birth risk of the women accepting sterility treatment is estimated.
Background technology
In the Therapeutic Method of clinical infertility, the tire parturition rate alive of auxiliary procreation technology (ART) each example treatment is the highest.Wo Lisi (Voorhis), New England Journal of Medicine (TheNewEnglandJournalofMedicine) the 356th phase page 379 to 386 (2007).From it comes out, the tire alive childbirth that the U.S. is annual there is 1% contribution having benefited from ART, for the newly-increased baby in this whole world more than 1,000,000.Nation all strangles (Bonduelle) et al., human reproduction (Human Reproduction) (England, Oxford) the 20th phase page 413 to 419 (2005 years)；Sunderland nurse (Sunderam) et al., incidence and mortality weekly (MMWRSurveillSumm) the 58th phase page 1 to 25 (2009).But, have many to be associated with medical science that ART implements, socioeconomic and ethical challenge has been resolved not yet.Such as, health, emotion and economically the cost caused due to treatment so that a pair man and wife ART to be carried out or the decision that ART to be repeated treats after the most failed trial usually become a difficult decision.Additionally, ART step cannot assure that result is live tire childbirth event, multiple birth event, or the relevant mother being associated to tire childbirth alive or multiple birth event/fetus/generation of neonatal complication.
For multiple pregnancy, accounting for the 3% of U.S.'s total population compared to it, within 2006, in the U.S., ART disproportionately account for the 18% of multiple pregnancy, and wherein the gestation of 17% is twins, the multiple birth that gestation is triplet or greater number of 38%；Therefore the ART baby of 49% is born by multiple pregnancy.Sunderland nurse et al., source is the same.Additionally, 2006 in the U.S., the early productivity of the whole nation compared to 13%, the birth of the ART baby of 41% is premature labor, and therefore, ART account for the 4% of all preterm deliveries of the U.S..Sunderland nurse et al., source is the same；Osterman (Osterman) et al., country's vital statistics report (NationalVitalStatRep) the 57th phase page 1 to 104 (2009).It is higher that the preterm delivery of many ART can be directly attributed to the incidence rate of multiple pregnancy in ART.For example, in 2006, accounting for the 11% of U.S.'s total population compared to preterm delivery number, the ART twins of 65% and the ART unit cell tire of 13% are all preterm deliveries.Similarly, accounting for the 6% of U.S.'s total population compared to low birth weight number, the ART twins of 57% and the ART connatae birth weight of unit cell tire of 9% are on the low side.Sunderland nurse et al., source is the same.Potentially including, although by total population, the childbirth caused by ART and non-ART ovarian stimulation makes these national statistics data may underestimate difference, but described national statistics data show that the risk of ART crowd's preterm delivery and multiple pregnancy is higher.
Many researchs all report disadvantageous obstetrics and neonatal result risk in the twins childbirth caused by ART and increase.During nineteen ninety-five to 2000 year from Denmark IVF/ICSI(external fertilization/intracytoplasmic sperm injection) during the exemplary research report based on ART childbirth of registration center and its country's medical science birth registration center (NationalMedicalBirthRegistry) gives a birth at 8602, having 40% is twins, and 60% is unit cell tire.Ping Boge (Pinborg) et al., Scandinavia gynecology and obstetrics' journal (ActaObstetriciaetGynecologica Scandinavica) the 83rd phase page 1071 to 1078 (2004).ART twins risk of premature labor before 37 pregnant weeks is 10 times of ART unit cell tire, and the risk of premature labor is 7.4 times of ART unit cell tire before 32 pregnant weeks.In Britain, the risk of birth weight that ART twins is on the low side (less than 2500 grams) increases to 11 times, and the risk of extremely low birth weight (less than 1500 grams) increases to 5 times.Su Lifu (Sutcliffe) et al., lancet (Lancet) the 370th phase page 351 to 359 (2007).Additionally, for ART gestation, stillbirth, cesarotomy and enter NICU(neonatal intensive care unit) incidence rate also can rise.In the same manner, similar discovery is also reported by many ART centers.
At present, for multiple birth event, do not exist through the forecasting tool verified in order to polytocous risk is estimated in the case of having two or more embryo transfer.It is challenging by the effort of multiple birth risk minimization, this is because lack optimal method at present to select patient to carry out selectivity list embryo transfer (eSET), by this eSET process, can by single embryo transfer to the uterus of ascetic patient thus be completely eliminated and nourish two twinborn risks of germ cell (this is the main cause of multiple pregnancy) and therefore reduce the risk of the preterm delivery caused by multiple pregnancy in ART.Although some report eSET can reduce multiple pregnancy rate simultaneously without compromising on tire parturition rate of living, but other people find tire parturition rate alive that is that the enforcement of eSET compromises each cycle or that accumulate, and cannot reduce multiple pregnancy rate.Card Shandong (Kalu) et al., Britain's journal of obstetrics and gynecology (BJOG) the 115th phase page 1143 to 1150 (2008)；Card pressgang (Khalaf) et al., Britain's journal of obstetrics and gynecology (BJOG) the 115th phase page 385 to 390 (2008)；Stevr (Styer) et al., fertility and infertile (FertilityandSterility) the 89th phase page 1702 to 1708 (2008).
Fertility doctor would generally discuss polytocous risk with their patient before starting IVF or other fertility treatments, and subsequently before carrying out embryo transfer (ET), i.e. before the action carrying out returning embryo transfer uterus, this risk can be discussed again.The embryo number purpose discussion relating to transplanting between doctor and patient is normally based on polytocous probability, the discussion of the conceived quality with the relation of female age, the number of the embryo of transplanting and embryo.When decision is to use many embryos or eSET, doctor would generally observe the instructional criterion that U.S. reproductive medicine meeting (ASRM) propose.ASRM selects the instructional criterion set up to be mainly based upon the age of women and total embryo number purpose for eSET patient.Fertility and the infertile 90th phase S163 to 164 page (2008).Possibly due to appreciate the limitation of these instructional criterions, ASRM it is also recommended that each ART center uses the data of himself to instruct the embryo's number for transplanting.
The instructional criterion set up in accordance with ASRM or Center for Disease Control (CDC) (CDC), doctor and their patient currently attempt reducing the polytocous incidence rate caused by IVF, and its method is if not transplanting single embryo, then transplanting less embryo.But there is a kind of general view, i.e. eSET can reduce the probability of tire alive childbirth, but is not known whether to there is the particular patient subset that multiple birth risk is higher.For example, it is possible that the polytocous risk of some patient may be the lowest, but if they have carried out eSET rather than have used two embryo transfers, then the probability of their tire alive childbirth may significantly be damaged.On the contrary, the polytocous risk of other patients may be of a relatively high, then uses eSET may reduce the health risk of they household largely.At present, method is not also had to may determine that a specific female patient whether being benefited more than another patient from eSET.
Discussed above confirm that multiple birth is a great healthy and socioeconomic problem for the patient accepting sterility treatment, and prior art cannot provide effective method to avoid multiple birth and/or to guarantee the success rate of eSET.
Summary of the invention
The shortcoming that instant invention overcomes prior art, method is to provide a kind of analytical data that comprises with the method predicting the multiple birth event of the female patient accepting sterility treatment, wherein said data are to choose from the group being made up of following item: the age of patient, the race of patient, the medical history of patient and childbearing history, the age of the male partner of patient, the race of the male partner of patient, the medical history of the male partner of patient and childbearing history, patient controls the reaction of reagent to hormone, the number of the oocyte obtained at patient, the number of the embryo obtained at patient, the quality of oocyte, the quality of ovum, the quality of sperm, the quality of fertilization, the quality of embryo, fetal development parameter, fetology lab scenario, sterility treatment scheme, and combinations thereof.
In one embodiment of the present invention, the childbearing history of patient can choose from the group being made up of following item: the conceived history of patient, the infertile history of patient, relates to the clinical diagnosis of patient's infertility, laboratory test, diagnosis or prognostic assay, and combinations thereof.The childbearing history of the male partner of patient would generally include sperm analysis.
In another embodiment of the present invention, it is to choose from the group being made up of following item that hormone controls reagent: gonadal hormone and progestogen, GuRH-A, antagonists of gonadotropin-releasing hormone, and promoting sexual gland hormone.Gonadal hormone and progestogen can choose from the group being made up of following item: estradiol, progesterone, and combinations thereof.The manipulation of hormone can include the treatment that the amount of the sex steroid being controlled the serum levels of sex steroid and/or being contacted germinal tissue is adjusted.
In further embodiment of the present invention, fetal development parameter is to choose from the group being made up of following item: morphology, cell number, stage of development, growth level, the molecular marker of growth, and combinations thereof.
In another embodiment of the present invention, sterility treatment method is to choose from the group being made up of following item: external fertilization (IVF), intracytoplasmic sperm injection (ICSI), and combinations thereof.
In further embodiment of the present invention, data can be obtained from single clinic or from multiple clinics.
In another embodiment of the present invention, the prediction of multiple birth event triggers embryo survival aptitude tests event, leads over embryo survival aptitude tests event, or allows embryo survival aptitude tests event to carry out.
In further embodiment of the present invention, multiple birth prediction data analysis is that the technology by choosing from the group being made up of following item performs: logistic regression, regression tree analysis, propelling tree are analyzed, and machine learning.
In another embodiment of the present invention, can be by data inputting to the software application containing at least one algorithm, at least one algorithm wherein said can choose from the group being made up of following item: logistic regression, regression tree analysis, propelling tree are analyzed, and machine learning.The operation of described software application can be real-time or in batches.
In further embodiment of the present invention, software application is integrated in a platform, the group that the choosing of this platform is freely formed with lower platform: desktop computer, notebook computer, network, network software are i.e. served by, the application of Cloud Server, the server that coexists, home server, storage medium, mobile device, smart mobile phone, the hand held device in clinical setting, electronic health record, and medical treatment device.Described medical treatment device is selected from the group being made up of following device: ultrasonic drilling machine, microscope, quality control apparatus, and diagnostic device.
In another embodiment of the present invention, the data being entered in algorithm relate to the data of one or more embryos of female patient, described data are selected from the group being made up of following item: the information obtained from the culture medium of one or more embryos, the survival ability information obtained from the non-intrusive digital imaging of one or more embryos, the information obtained from bioptic embryonic cell or cell debris, the gene expression analysis of one or more embryos, the genome analysis of one or more embryos, the methylation sites analysis of one or more embryos, the Proteomic analysis of one or more embryos, and combinations thereof.Cell debris is selected from the group being made up of following item: polar body, blastomere, the cell of degraded, the embryo of lower level, and Trophectoderm cells.
In further embodiment of the present invention, the information obtained from culture medium is to choose from the group being made up of following item: the metabolite in culture medium, the protein of secretion, the peptide of secretion, lipid, carbohydrate, oxygen-derived free radicals, gas form, dissociative DNA, free RNA, and combinations thereof.
In another embodiment of the present invention, the survival ability information obtained from the non-intrusive digital imaging of one or more embryos is to choose from the group being made up of herein below: cell division speed, the morphometry of subcellular structure, embryonic cell morphometry relative to each other, embryonic cell position relative to each other, cell division is relative to just in the direction of somatoblast position, embryonic cell split coil method is for the direction of cell mass position, the density of subcellular structure, the spatial distribution of intracellular subcellular structure, subcellular structure is relative to the spatial distribution of cell mass, and combinations thereof.
In further embodiment of the present invention, genome analysis is to choose from the group being made up of following item: the chromosome analysis of whole genome sequence, the chromosome analysis of partial genome sequence, transcriptome analysis, copy number analysis of variance, and single nucleotide polymorphism (SNP) is analyzed.Genome analysis can be chemically examined by one and perform, described chemical examination is to choose from the group being made up of following item: fluorescence in situ hybridization (FISH), comparative genome hybridization (CGH), polymerase chain reaction (PCR), the real-time PCR of sxemiquantitative, multiplex PCR, oligonucleotide or oligonucleotide arrays, antibody array, and chromatin imrnunoprecipitation reaction.
In another embodiment of the present invention, methylation sites analysis is in the group of choosing freely following item composition: complete genome DNA methylates, specific gene DNA methylation, and combinations thereof.
In further embodiment of the present invention, the analysis obtained from multiple birth is predicted is applied on diagnosis or pre-rear platform or device predict the embryo survival ability of female patient.The feature of the one or more physiological, gene of embryo or growth is generally measured by described diagnosis or pre-rear platform or device, described feature is selected from the group being made up of following item: the Methanogenesis of embryo, the genetic flaw of embryo, the genovariation of embryo, the chromosome deficiency of embryo, the chromosomal structural variation of embryo, the transcription group collection of illustrative plates of embryo, the speed of embryonic cell division, Morphologic Parameters, the measurement of growth in culture medium, and combinations thereof.Morphologic Parameters can pass through microscope imaging, videoscope imaging, or a combination thereof and determine.
Other aspects of the present invention and embodiment are by the detailed description of the unrestricted present invention being set forth in and being presented below.
Detailed description of the invention
Be presented below is the description of the preferred embodiment being presently believed that to the present invention advocated.Replacement or amendment in any function, purposes or structure are intended to be contained by the claim of patent application document.In this explanation and claims, singulative " ", " one " and " described " include plural form, unless context otherwise explicitly points out.In this explanation and claims, term used " includes " indicating and there are described feature, entirety, step, operation, element and/or parts, but is not precluded from existing or adding other features one or more, entirety, step, operation, element, parts and/or the combination of above-mentioned item.
In the context of the present invention, term " patient " refers to accept the women of sterility treatment.
Term " sterility treatment " refers to use the oral or drug-induced ovulation of injection or stimulate ovary to produce more than one mature egg cell (that is, can carry out being fertilized to generate the ovum of embryo).In the context of the present invention, term " sterility treatment " is intended to include by artificial fertilization, IVF, and/or the natural conception that ICSI assists.Term " sterility treatment " increases the cycle that is natural, induction or that stimulate by cycle monitoring in the case of alsoing attempt to be included in presence or absence medical intervention or medicine, for this situation, the purpose of sterility treatment is to improve and breeds in vivo (such as, after artificial fertilization or pass through free period) or the survival ability of embryo thawing at IVF, ICSI, Embryo freezing preservation or being transplanted in uterus after any other auxiliary procreation technology.
Term " auxiliary procreation technology " and " ART " refer in vitro the treatment of (outside health) manipulation gamete (being in ovum and the sperm in any maturation period).The main Types of ART includes but not limited to: (i) external fertilization (IVF), and it needs underwent operative taken out from health by ovum and be fertilized in vitro, cultivates embryo the most in vitro and is returned in health by embryo transfer；(ii) intracytoplasmic sperm injection (ICSI), this technology is similar to IVF, its difference be sperm by independent microinjection to each ovum to evade natural fertilization process；(iii) gamete intra-Fallopian transfer (GIFT), the ovum wherein taken out or treated sperm are placed in fallopian tube in an operation process (laparoscopy), and fertilization and pregnancy occur the most in vivo；(iv) the freezing embryo from IVF or ICSI process is used；V () uses the ovum from women donor；(vi) sperm from male donor is used；(vii) embryo is put in the uterus of foster mother, and (viii) uses freezing ovum (rather than embryo) or sperm.
Term " multiple birth event " refers to two or more fetuses or the childbirth of baby in the single pregnancy at least up to 20 gestation weeks, regardless of connatae each fetus or the individual survival ability of postnatal each baby.By contrast, term " multiple pregnancy event " refers to the common survival ability of two or more embryo, said two or multiple embryo are transplanted in uterus, and can grow any stage of pregnancy, and in these stages, one or more embryos may become dead or continue as survival.In the context of the present invention, multiple birth event is intended to encompass and includes multiple pregnancy event.The direct result of sterility treatment (can include one or more auxiliary procreation technology by definition) is that multiple birth event would generally occur.It should be understood that term " multiple birth event " is different from " tire childbirth of living ", " tire parturition rate of living " or " tire childbirth event of living ", all these contents refer to the successful treatment so that surviving baby due.Such as, discussions about " live in tire childbirth " is typically to pay close attention to a treatment in the category of sterility treatment the most successfully rather than whether it produces multiple birth or superpregnant and relevant complication thereof.
Term " MBP " or " MBP prognostic tool " can alternate the multiple birth prediction experiment made for referring to the present invention
Term " posteriority logarithm of the odd score，LOD score (posteriorlogofoddsratio) " or " PLORA " test use Bayesian statistic, log-likelihood or additive method to calculate posterior probability.Additionally, be used as other posterior probability methods such as log-likelihood, relative log-likelihood, and/or the improvement of log-likelihood.
Differentiation power is measured under a series of threshold values arbitrarily defined by term " area under curve " or " AUC " based on true and false positive rate.How term " receiver operating curves " or " ROC " measure the test balance to predicting when between the ability and the true probability occurred of prediction that result can occur.In prognosis, AUC/ROC measures differentiation power, i.e. the separating capacity of forecast model patient with the patient with preferable prognosis to having poorer prognosis.In the context of the present invention, the area under AUC refers to ROC curve.At its best, when predicting result (that is, True Positive Rate be 100% and false positive rate is 0%) of 100%, AUC=1, AUC=5 indicate prediction almost as toss a coin, and when AUC < when 0.5, indicates prediction more worse than toss a coin.
In IVF treats, it is generally recognized that the number of the embryo transplanting back patient determines the number of gestation or natus largely.Multiple birth prediction (MBP) prognostic tool of the present invention is able to determine whether to transplant certain number of embryo to cause the Clinical pregnancy that can survive and finally to cause tire childbirth event of living.Such as, can use MBP prognostic tool on the same day of transplanting embryo, to inform patient, they are having two or more embryo to be transplanted to polytocous individuation risk in the IVF treatment in uterus.In order to run MBP prognostic tool, use patient-specific data that multiple pregnancy event, multiple birth event, and/or the survival ability of certain number of embryo can carry out personalized assessment.
One advantage of the MBP prognostic tool of the present invention is that it can have the patient of more much higher tire risk of pregnancy to those, and/or those patients being carried out eSET by strong preference are identified.By providing the patient-specific risk of multiple birth event, eSET is more likely estimated by patient.It is lower that the patient using eSET stands the probability of associated neogenesis complication with multiple birth event, these complication such as, premature labor, low birth weight, preeclampsia, and miscarriage.Although single embryo transfer can cause multiple birth event (typically monozygotic twins, its equally relevant in obstetrics and neonatal complication), but be substantially less than by the universality transplanting the multiple birth event that multiple embryos cause by transplanting the monovular twins universality that causes of single embryo.
By using MBP prognostic tool with approach described herein, patient and the doctor identification to the embryo of most survival ability can be strengthened, the most only transplant the probability that one or two embryo can't damage the tire alive childbirth event of single IVF treatment.Alternatively or additionally, if the MBP prognostic tool of the present invention can be used for more than one embryo be transplanted in uterus (if or use in the treatment natural conception or during artificial fertilization ovulation produce more than one ovum) time identify the patient occurring multiple birth event risk of a relatively high.This type of patient is benefited most from performing the embryo survival aptitude tests for selecting the embryo of most survival ability to carry out transplanting.
For running the data of the MBP prognostic tool of the present invention including but not limited to the age of patient, the race of patient, the medical history of patient and childbearing history, the age of the male partner of patient, the race of the male partner of patient, the medical history of the male partner of patient and childbearing history, patient controls the reaction of reagent to hormone, the number of the oocyte obtained at patient, the number of the embryo obtained at patient, the quality of oocyte, the quality of ovum, the quality of sperm, the quality of fertilization, the quality of embryo, fetal development parameter, fetology lab scenario, sterility treatment scheme, and combinations thereof.
The manipulation of hormone generally includes the treatment that the sex steroid amount being contacted germinal tissue is controlled or regulates.The reaction that hormone is manipulated by patient may include but be not limited to: endometrium thickness (by ultrasonic measurement) and/or peak serum estradiol level.Hormone control reagent under the present invention expects includes but not limited to: gonadal hormone and progestogen (such as, estradiol and progesterone), GuRH-A, antagonists of gonadotropin-releasing hormone, and promoting sexual gland hormone.Fetal development parameter under the present invention expects includes but not limited to: morphology, cell number, the stage of development,
Grow level, the molecular marker of growth, and combinations thereof.
Directly from patient, the paper chart of clinic, electronic health record, electronic personal health records, and the combination of foregoing can obtain data.Generally prepared by health care provider, patient or user for running the data of MBP prognostic tool, or jointly prepared with patient by health care provider.In a preferred embodiment, report will use user it will be appreciated that language to provide test description, its explain and limitation, and figure shows to assist a physician and communication between patient.
In one embodiment of the present invention, multiple birth prediction data analysis is that the technology by choosing from the group being made up of following item performs: logistic regression, regression tree analysis, propelling tree are analyzed, and machine learning.In another embodiment of the present invention, can multiple birth prediction data be entered in the software application containing at least one algorithm, at least one algorithm wherein said may include but be not limited to: logistic regression, regression tree analysis, the analysis of propelling tree, machine learning.The data being entered in algorithm can relate to the data of one or more embryos of female patient, described data include but not limited to: the information obtained from the culture medium of one or more live body embryos, the survival ability information obtained from the non-intrusive digital imaging of one or more embryos, the information obtained from bioptic embryonic cell or cell debris, the gene expression analysis of one or more embryos, the genome analysis of one or more embryos, the methylation sites analysis of one or more embryos, the Proteomic analysis of one or more embryos, and combinations thereof.The example of cell debris includes but not limited to: polar body, blastomere, the cell of degraded, the embryo of lower level, and Trophectoderm cells.
The example of the information obtained from embryo culture medium includes but not limited to: relate to the metabolite such as ammonium and glucose, the protein of secretion, the peptide of secretion, lipid, carbohydrate, oxygen-derived free radicals, gas composition, dissociative DNA and the information of free RNA.According to the difference of patient's multiple birth event risk, useful degree and quantitative (or sxemiquantitative) level thereof of described information are likely to difference.The example of gene expression includes but not limited to Oct4, Sall4 and Nanog expression.The example of genome analysis includes but not limited to: the chromosome analysis of whole genome sequence, the chromosome analysis of partial genome sequence, transcriptome analysis, copy number analysis of variance, and single nucleotide polymorphism (SNP) is analyzed.The example of the chemical examination performing said gene group analysis includes but not limited to: fluorescence in situ hybridization (FISH), comparative genome hybridization (CGH), polymerase chain reaction (PCR), the real-time PCR of sxemiquantitative, multiplex PCR, oligonucleotide or oligonucleotide arrays are (i.e., " gene chip "), antibody array, and chromatin imrnunoprecipitation reaction.It should be understood that proposed genome analysis and chemical examination can be not only used for genomic DNA can be used for again geneome RNA.The example of methylation sites analysis includes but not limited to: complete genome DNA methylates and specific gene DNA methylation.
The example of the non-invasive analysis of embryo is the digital image of embryo, and it is one or more that it can measure in the following characteristics of embryo: cell division speed, the morphometry of subcellular structure, embryonic cell morphometry relative to each other, embryonic cell position relative to each other, cell division relative to just in the direction of somatoblast position, embryonic cell split coil method for direction, the density of subcellular structure, the spatial distribution of intracellular subcellular structure and the subcellular structure of cell mass position relative to the spatial distribution of cell mass.
In another embodiment of the present invention, it is thus achieved that can be entered in the software application containing MBP algorithm for the data running MBP prognostic tool, described software application can be ordered to run in real time or in batches.Find by other fertilities Clinical Decision Support Systems (CDSS) and embryo transfer (ET) are carried out contrast, interval between the time that all of clinical data can be used in time of decision-making and ET must occur is the least, correspondingly, software application must by patient and doctor thereof ready-made use.In one embodiment of the present invention, software application is integrated in a platform, this platform may include but be not limited to: desktop computer, notebook computer, network, network software are i.e. served by, Cloud Server, the server that coexists, storage medium (such as, CD, memory stick or thumb actuator), mobile device, smart mobile phone application, the hand held device in clinical setting, electronic health record, or medical treatment device.The example that can be used for depositing the medical treatment device of the MBP prognostic tool of the present invention includes but not limited to: ultrasonic drilling machine；Used to support the device of In vitro culture, such as, microscope, quality control apparatus, and diagnostic device by clinical fetology laboratory, such as, for device embryo survival ability being analyzed and report.
The MBP prognostic tool of the application of the invention, doctor can discuss with IVF patient with regard to the selection of eSET and the risk of multiple birth event based on predictive models, to provide the assessment of the personalized probability of multiple birth event, the exploitation of described model and checking are by different cases and patient are analyzed acquisition.By using whether the personalized prediction of multiple birth probability, patient and doctor just can use this one side of Embryo selection to make informed decision-making based on embryo survival ability test.Such as, if the risk of multiple birth event is the highest, then embryo survival ability test is exactly very favorable for patient such that it is able to it is determined that be transplanted to the number of live embryo in the patient to avoid multiple birth event.On the contrary, if the risk of multiple birth event is relatively low, the cost-benefit ratio of embryo survival ability test is so used to be limited, this is because regardless of the survival ability of the embryo being transplanted in the patient and number, patient's the most unlikely generation multiple birth event.Owing to embryo survival ability test is typically an expensive process, so grasping evidential method to recommend embryo survival ability test to be discussion and a very important part in steps in decision-making to patient.
The MBP prognostic tool of the present invention can carry out the following content: (i) has the IVF patient of higher multiple birth risk when identifying and transplant two or more embryo；(ii) compared to eSET, the IVF patient that when transplanting two embryos, multiple birth risk will not change is identified；(iii) the IVF patient that its probability living tire childbirth result seriously can be damaged by eSET is identified；(iv) the IVF patient that its probability living tire childbirth result will not be affected by eSET is identified；V () identifies and belongs to the IVF patient in any two group listed above, and (vi) and just supported the most personalized discussion before starting IVF before ET.
In one embodiment of the present invention, the MBP prognostic tool of the present invention is applied on diagnosis or pre-rear platform or device be predicted with the embryo survival ability to female patient.The diagnosis can being used together with the MBP prognostic tool of the present invention or pre-rear platform generally will measure one or more parameter, and this parameter includes but not limited to the physiological, gene of embryo and the feature grown.Embryo's is physiological, gene, and/or the feature grown is typically included parameter, such as, the measurement of speed, Morphologic Parameters and the growth of the Methanogenesis of embryo, the genetic flaw of embryo, the genovariation of embryo, the chromosome deficiency of embryo, the chromosomal structural variation of embryo, the transcription group collection of illustrative plates of embryo, embryonic cell division in culture medium.Microscope imaging and/or videoscope imaging is generally used to carry out the research of Morphologic Parameters.
The prediction of multiple birth risk and the relative importance of prediction of the particular patient in specific sterility treatment are probably different in some clinics.Difference between clinic includes but not limited to: the difference of the process of the difference of therapeutic scheme, the difference of fetology lab scenario, cultivation oocyte and embryo (that is, IVF is compared to ICSI)；Embryo selection standard is transplanted or the difference of freezen protective；The difference of physical environment；The difference of instrument calibration；And the difference of embryo transplantation method.MBP prediction and its importance associated clinic between difference show that the prognostic clinical factors in a clinic may not have identical prognostic value in a different clinic.
In one embodiment of the present invention, the exploitation of MBP prognostic tool and checking are to develop for single clinic and verify.As proprietary clinic prognostic tool, MBP is only used for this specific clinic.In another embodiment of the present invention, MBP prognostic tool empirical tests is also applied in multiple clinic.As multiple clinics prognostic tool, MBP is preferably used for scheme and has the clinic of intercommunity, making identical clinic variable is prognosis for each clinic, and the relative importance of these prognostic factors is substantially similar to for each clinic, therefore these clinics use identical MBP to be rational.In the context of the present invention, can be initial data self for preparing the data of single or multiple clinics forecasting tool, or in the case of more appropriate, the impact on multiple birth probability for the relationship between data and/or data.
Owing to the MBP prognostic tool of the present invention depends on clinical protocol, clinical practice type and the selection standard to the patient carrying out eSET or embryo survival aptitude tests, and all these equal relative prognostic value of clinical variable of may affecting, therefore along with clinical protocol or the change of its patients, MBP can change therewith.On this point, it may be necessary to periodic variation MBP prognostic tool thus in view of clinical protocol, put into practice type, and patient and eSET select the change recently of standard.In a preferred embodiment of the present invention, MBP prognostic tool is carried out annual review.
Although it should be understood that combine embodiment proposed above, present invention is described, but described above and hereinafter example is intended to describe and unrestricted the scope of the present invention.Further, it should be understood that embodiments set forth herein and example are not detailed, and without departing from the scope and spirit in the present invention, the present invention can be made various modifications and variations by one of ordinary skill in the art.
All of patent mentioned in this article and publication are incorporated by herein the most by reference.
Experiment
Following Examples is proposed to provide the complete disclosure how producing and utilizing each aspect of the present invention presented herein and every embodiment to one of ordinary skill in the art.Unless otherwise stated, the part that part is by weight, temperature is Celsius temperature, and pressure is atmospheric pressure or close to atmospheric pressure.Unless otherwise stated, all of assembly is all commercially available.
Example 1
MBP model and the generation of age Controlling model
Prepare MBP model and the methodology of age Controlling model
Regression tree and advance tree method for serious, the nonredundant prognostic factor that affect multiple birth risk in ART crowd are identified.The prognostic factor that regression tree and propelling tree method are identified is for generating MBP model described herein and age Controlling model.
MBP model builds in the IVF treatment that one group of number is 250 to 500, and tire of wherein living childbirth result is caused in female patient body by by least two embryo transfer.
For external certificate, MBP model builds in the IVF treatment that one group of number is 100 to-250, and tire of wherein living childbirth result is caused in female patient body by by least two embryo transfer.
MBP model, i.e. MBP-1 generate according to abovementioned steps.Controlling model uses the age to predict polytocous probability as unique Prognostic Factors.The ultimate principle using the actual age of patient is according to ASRM criterion, and the age is for assessing multiple birth risk and selecting the principal element of single embryo transfer (eSET) patient.
Following statistics relatively in MBP-1 is compared with age Controlling model.Result confirms that the age (that is, the principal element that sASRM Yu the CDC criterion that eSET selects is proposed) of patient is not the important predictive factors of multiple birth risk in IVF.
Example 2
MBP model compares with the statistics of age Controlling model
PLORA tests
PLORA test calculates for posterior probability polytocous with the prediction under age Controlling model to MBP-1, and content is as follows:
The PLORA of MBP-1 is 3.0(logarithmic scale) and 20(lineal scale).
The improvement that statistics conclusion: MBP-1 provides multiple birth result compared to age Controlling model with the ratio of 20:1 is joined suitable.
Explain: MBP-1 in terms of multiple birth result improvement predictive ability is age Controlling model 20 times in IVF.
The PLORA of age Controlling model is set to 0(logarithmic scale) and 1(lineal scale).
Example 3
MBP model compares with the statistics of age Controlling model
AUC/ROC tests
Compared with only using age models, the improved capacity that the patient with different multiple birth risks is made a distinction in the novel IVF-ET treatment use at least two embryo by AUC/ROC test for prediction, content is as follows:
The AUC of MBP-1 is equal to 0.70；The AUC of age Controlling model is equal to 0.6.
Compared with the model only using the age, MBP-1 improves 16.7% to the separating capacity of the patient with different multiple birth risks in the novel IVF-ET treatment use at least two embryo.
Example 4
MBP model compares with the statistics of age Controlling model
Prediction dynamic range and classify again
In addition to statistical analysis, the suitability of prognostic tool also relies on the dynamic range of prediction probability and it may happen that the ratio of patients of " classifying again ", needs to carry out " to classify and " be because these patients to have dramatically different (or rather) and compare the multiple birth probability of age Controlling model.
Can by MBP-1 model inform the dynamic range of its polytocous particular probability of patient about 10% between more than 60% rather than the age based on patient informs in its polytocous three probability in the range of about 20% to about 40% of patient one.Use the MBP-1 model of example 1, less than the 42 years old patient of about 58% can be classified again, so that they have and only use the age to be predicted different multiple birth probability.
Example 5
The analysis of the common survival ability of embryo
The female patient receiving sterility treatment has 7 embryos and has to decide on the one or more embryos of transplanting.This patient accepts embryo survival ability test on the one or more diagnostic platforms using bioanalysis (such as, embryo's biopsy), to perform unicellular gene expression analysis, such as, and a cell of biopsy from each embryo.Receive embryo's biopsy to report and provide the probability of pregnancy to patient and health care provider thereof or the tire alives of each in 1 to 7 embryos that patient will carry out in the case of an embryo transfer is given a birth probability.
By applying the MBP method of the present invention, patient also receives the probability report of the multiple birth event in the case of having transplanted any two embryo, therefore informs patient and which two embryo of health care provider can provide optimal tire alive childbirth probability and minimize the probability of multiple birth event simultaneously.

Claims (30)

1. the computer being used for analyzing the data relevant to (before ET) step before the embryo transfer of IVF process System, described computer system comprises the computer hardware application for logging data, and described data are from by following item institute The group of composition chooses: the age of patient, the race of patient, the medical history of patient and childbearing history, the man of patient The age of sex partner, the race of male partner of patient, the medical history of male partner of patient and childbearing history, patient are to swashing Element controls the reaction of reagent, the number of oocyte obtained at patient, the number of embryo obtained at patient, ovum The quality of blast cell, the quality of ovum, the quality of sperm, the quality of fertilization, the quality of embryo, fetal development parameter, Fetology lab scenario, sterility treatment scheme, and combinations thereof；And
Computer software application, described computer software application is analyzed described data and was walked before the ET of prediction IVF process There is the probability of the multiple birth event from IVF process in rapid female patient, wherein said software application contains at least A kind of algorithm and its operation are real-time or in batches, the prediction of wherein said multiple birth event triggers described female Property patient embryo survival aptitude tests event, lead over the embryo survival aptitude tests event of described female patient, or permit The embryo survival aptitude tests event being permitted described female patient is carried out, and is wherein transplanted to described female patient The selection of live embryo is prediction based on described multiple birth event.
Computer system the most according to claim 1, the childbearing history of wherein said patient is to be formed from by following item Group in choose: the conceived history of patient, the infertile history of patient, relate to the clinical diagnosis of patient's infertility, laboratory Test, diagnostic or prognostic assay, and combinations thereof.
Computer system the most according to claim 1, the childbearing history of wherein said patient's male partner includes that sperm divides Analysis.
Computer system the most according to claim 1, wherein said hormone controls reagent and forms from by following item Group chooses: gonadal hormone and progestogen, GuRH-A, gonadotropin releasing hormone Antagonist, and promoting sexual gland hormone.
Computer system the most according to claim 4, wherein said gonadal hormone and progestogen are to form from by following item Group in choose: estradiol, progesterone, and combinations thereof.
Computer system the most according to claim 1, wherein hormone manipulation includes entering the serum levels of sex steroid The treatment that row controls.
Computer system the most according to claim 1, wherein hormone manipulation includes the property class being contacted germinal tissue The treatment that the amount of sterin is adjusted.
Computer system the most according to claim 1, wherein said fetal development parameter forms from by following item Group chooses: morphology, cell number, stage of development, growth level, the molecular marker of growth, and combinations thereof.
Computer system the most according to claim 1, wherein said sterility treatment scheme is to form from by following item Group in choose: external fertilization (IVF), intracytoplasmic sperm injection technology (ICSI), and combinations thereof.
Computer system the most according to claim 1, wherein said data obtain from single clinic.
11. computer systems according to claim 1, wherein said data obtain from multiple clinics.
12. computer systems according to claim 1, wherein said multiple birth prediction data analysis be by from by The technology chosen in the group that following item is formed performs: logistic regression, regression tree analysis, propelling tree are analyzed, with And machine learning.
13. computer systems according to claim 1, wherein said data are entered into containing at least one algorithm In software application.
14. computer systems according to claim 13, at least one algorithm wherein said is from by following item institute group The group become chooses: logistic regression, regression tree analysis, the analysis of propelling tree, machine learning.
15. computer systems according to claim 14, the data being wherein entered in described algorithm are described for relating to The data of one or more embryos of female patient.
16. computer systems according to claim 15, the data being wherein entered in described algorithm be choosing freely with In the group that lower information is formed: the information that obtains from the culture medium of one or more embryos, from one or more embryos' In non-intrusive digital imaging obtain survival ability information, obtain from bioptic embryonic cell or cell debris Information, the gene expression analysis of one or more embryo, the genome analysis of one or more embryo, one or more The methylation sites analysis of embryo, the Proteomic analysis of one or more embryo, and combinations thereof.
17. computer systems according to claim 16, the described information wherein obtained from described culture medium be from The group being made up of following item chooses: the metabolite in culture medium, the protein of secretion, the peptide of secretion, fat Class, carbohydrate, oxygen-derived free radicals, gas composition, dissociative DNA, free RNA, and combinations thereof.
18. computer systems according to claim 16, wherein from the described non-intruding of the one or more embryo Property digital image in obtain described survival ability information be to choose from the group being made up of following item: cell divides Split speed, the morphometry of subcellular structure, embryonic cell morphometry relative to each other, embryonic cell relative to that This position, cell division relative to just in the direction of somatoblast position, embryonic cell split coil method is for cell mass position Direction, the density of subcellular structure, the spatial distribution of intracellular subcellular structure, subcellular structure is relative to cell mass Spatial distribution, and combinations thereof.
19. computer systems according to claim 16, wherein said cell debris is that choosing freely following item is formed Group in: polar body, blastomere, the cell of degraded, the embryo of lower level, and Trophectoderm cells.
20. computer systems according to claim 16, wherein said genome analysis is to be formed from by following item Group in choose: the chromosome analysis of whole genome sequence, the chromosome analysis of partial genome sequence, turn Record group analysis, copy number analysis of variance, and single nucleotide polymorphism (SNP) analysis.
21. computer systems according to claim 20, wherein said genome analysis is to be chemically examined by one to hold OK, described chemical examination is to choose from the group being made up of following item: fluorescence in situ hybridization (FISH), compare base Because of group hybridization (CGH), polymerase chain reaction (PCR), the real-time PCR of sxemiquantitative, multiplex PCR, oligonucleotide or core Thuja acid array, antibody array, and chromatin imrnunoprecipitation reaction.
22. computer systems according to claim 16, wherein said methylation sites analysis is choosing freely following item In the group of composition: complete genome DNA methylates, specific gene DNA methylation, and combinations thereof.
23. computer systems according to claim 13, the operation of wherein said software application is real-time.
24. computer systems according to claim 13, the operation of wherein said software application is in batches.
25. computer systems according to claim 13, wherein said software application is integrated in a platform, The group that described platform is formed selected from following item: desktop computer, notebook computer, network, network software i.e. take Business application, Cloud Server, the server that coexists, home server, storage medium, mobile device, smart mobile phone apply, Hand held device in clinical setting, electronic health record, and medical treatment device.
26. computer systems according to claim 25, wherein said medical treatment device is that choosing freely following item is formed Group in: ultrasonic drilling machine, microscope, quality control apparatus, and diagnostic device.
27. computer systems according to claim 1, wherein said multiple birth prediction data analysis is applied to diagnosis Or to predict the embryo survival ability of female patient on pre-rear platform or device.
Described in 28. computer systems according to claim 27, wherein said diagnosis or pre-rear platform or measurement device Embryo's is one or more physiological, gene, or the feature grown.
29. computer systems according to claim 28, one or more physiological, the gene of wherein said embryo , or in the group of the feature choosing grown freely following item composition: the base of the Methanogenesis of embryo, embryo in culture medium Because of defect, the genovariation of embryo, the chromosome deficiency of embryo, the chromosomal structural variation of embryo, the transcript profile of embryo Learn collection of illustrative plates, the speed of embryonic cell division, Morphologic Parameters, the measurement of growth, and combinations thereof.
30. computer systems according to claim 29, wherein said Morphologic Parameters is by microscope imaging, video Oscillograph imaging, or a combination thereof determines.
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